The present invention relates to a method of treatment for non-hematologic malignancies comprising the administration of anti-insulin-like growth factor I receptor (IGF-1R) antibodies, in conjunction with other therapeutic agents such as chemotherapeutic agents and hormonal therapy.
The insulin-like growth factor (IGF) signaling system plays an important role in the growth and development of many tissues and regulates overall growth. Insulin-like growth factor (IGF-1) is a 7.5-kD polypeptide that circulates in plasma in high concentrations and is detectable in most tissues. IGF-1 stimulates cell differentiation and cell proliferation, and is required by most mammalian cell types for sustained proliferation. These cell types include, among others, human diploid fibroblasts, epithelial cells, smooth muscle cells, T lymphocytes, neural cells, myeloid cells, chondrocytes, osteoblasts and bone marrow stem cells.
The first step in the transduction pathway leading to IGF-1-stimulated cellular proliferation or differentiation is binding of IGF-1 or IGF-2 (or insulin at supraphysiological concentrations) to the IGF-1 receptor. The IGF-1 receptor (IGF-1R) is composed of two types of subunits: an alpha subunit (a 130-135 kD protein that is entirely extracellular and functions in ligand binding) and a beta subunit (a 95-kD transmembrane protein, with transmembrane and cytoplasmic domains). IGF binding proteins (IGFBPs) have growth inhibiting effects by, at least in part, competitively binding IGFs and preventing their association with IGF-1F. The interactions between IGF-1, IGF-2, IGF1R, and IGFBPs affect many physiological and pathological processes such as development, growth and metabolic regulation.
The IGF-1R is initially synthesized as a single chain proreceptor polypeptide that is processed by glycosylation, proteolytic cleavage, and covalent bonding to assemble into a mature 460-kD heterotetramer comprising two alpha-subunits and two beta-subunits. The beta subunit(s) possesses ligand-activated tyrosine kinase activity. This activity is implicated in the signaling pathways mediating ligand action which involve autophosphorylation of the beta-subunit and phosphorylation of IGF-1R substrates.
There is considerable evidence for a role for IGF-1 and/or IGF-1R in the maintenance of tumor cells in vitro and in vivo. IGF-1R levels are elevated in tumors of lung (Kaiser et al., J. Cancer Res. Clin. Oncol. 119: 665-668, 1993; Moody et al., Life Sciences 52: 1161-1173, 1993; Macauley et al., Cancer Res., 50: 2511-2517, 1990), breast (Pollack et al., Cancer Lett. 38: 223-230, 1987; Foekens et al., Cancer Res. 49: 7002-7009, 1989; Cullen et al., Cancer Res. 49: 7002-7009, 1990; Arteaga et al., J. Clin. Invest. 84: 1418-1423, 1989), prostate and colon (Remaole-Bennet et al., J. Clin. Endocrinol. Metab. 75: 609-616, 1992; Guo et al., Gastroenterol. 102: 1101-1108, 1992). In addition, IGF-1 appears to be an autocrine stimulator of human gliomas (Sandberg-Nordqvist et al., Cancer Res. 53: 2475-2478, 1993), while IGF-1 stimulated the growth of fibrosarcomas that overexpressed IGF-1R (Butler et al., Cancer Res. 58: 3021-27, 1998). In addition, individuals with “high normal” levels of IGF-1 have an increased risk of common cancers compared to individuals with IGF-1 levels in the “low normal” range (Rosen et al., Trends Endocrinol. Metab. 10: 136-41, 1999). For a review of the role IGF-1/IGF-1 receptor interaction plays in the growth of a variety of human tumors, see Macaulay, Br. J. Cancer, 65: 311-320, 1992.
Numerous classes of antineoplastic agents are currently in use. Docetaxel, one of a group of drugs called “taxanes,” which are derived from the bark and needles of yew trees, is the first anticancer agent to show a significantly higher response rate than doxorubicin, a very active agent and widely used chemotherapy in the first-line treatment of metastatic breast cancer. Docetaxel also is the first chemotherapy drug as a single agent to demonstrate increased survival among patients with advanced breast cancer compared to the combination of mitomycin C and vinblastine, a commonly used regimen in this patient population. Median time to progression and time to treatment failure were significantly longer for docetaxel than for mitomycin C in combination with vinblastine, and the one-year survival rate significantly greater. Promising results have also been recorded for docetaxel in other human malignancies, such as ovarian, lung, head and neck, gastric and pancreatic cancers.
Paclitaxel, also a taxane, binds to microtubules and prevents their molecular disassembly, thereby inhibiting mitosis (cell division). With the spindle still in place the cell cannot divide into daughter cells. Paclitaxel is most effective against ovarian carcinomas and advanced breast carcinomas.
Hormonal therapy can be very effective in lowering the risk of recurrence for women with hormone-receptor-positive breast cancer. Tamoxifen is the hormonal therapy that has been around the longest—nearly 30 years. It blocks the effect of estrogen on breast cancer cells, keeping the cells from growing. Tamoxifen can reduce recurrence by 40-50% in post-menopausal women, and by 30-50% in pre-menopausal women. It also lowers the risk of a new breast cancer developing in the unaffected breast, and can slow down the progression of advanced disease.
In recent years, aromatase inhibitors have been used as hormonal therapy. This type of therapy is recommended only for postmenopausal women with hormone-receptor-positive breast cancer. It works by blocking the production of estrogen in muscle and fat tissue, which is the main source of estrogen in women beyond menopause, after which the ovaries stop making significant levels of estrogen.
Prostate cancer is the most common cancer and the second cause of cancer death in men in the United States. About 10% of the initial cases of prostate cancer present with metastatic disease. However, in the rest, metastases will develop despite treatment with surgery, radiation or medical therapy, and those metastases will eventually become refractory to hormonal treatment. The use of chemotherapy in hormone refractory (androgen independent) progressive prostate cancer (HRPC) has been characterized historically by poor efficacy and high toxicity. Newer regimens containing docetaxel have shown a survival benefit over previous palliative regimens. Despite this positive trend, the median survival of HRPC patients treated with docetaxel and prednisone is only 18.9 months; clearly, more effective regimens are required for the treatment of HRPC patients.
Although some currently available anti-cancer treatments have been successful, complete responses to these treatments are infrequently observed, and the patient population refractory to these treatments is still large. Thus, development of new therapeutic regimens, particularly those capable of augmenting or potentiating the anti-tumor activity of other anti-neoplastic agents, is necessary.
In view of the roles that IGF-1 and IGF-1R have in such disorders as cancer and other proliferative disorders when IGF-1 and/or IGF-1R are overexpressed, antibodies to IGF-1R have been produced that block binding of IGF-1 or IGF-2 to IGF-1R. Such antibodies are described, for example, in International Patent Application No. WO 02/053596, published Jul. 11, 2002; International Patent Application Nos. WO 05/016967 and WO 05/016970, both published Feb. 24, 2005; International Patent Application No. WO 03/106621, published Dec. 24, 2003; International Patent Application No. WO 04/083248, published Sep. 30, 2004; International Patent Application No. WO 03/100008, published Dec. 4, 2003; International Patent Publication WO 04/087756, published Oct. 14, 2004; and International Patent Application No WO 05/005635, published Jan. 26, 2005. Because of their ability to block a tumor cell survival pathway, it is desirable to use such anti-IGF-1R antibodies to treat cancer, particularly non-hematological malignancies, in patients to obtain an improved clinical benefit relative to standard cancer treatment regimes alone.